Gnrh analogues for treatment of urinary incontinence

ABSTRACT

The use of at least one GnRH analogue for the preparation of a medicament for the prevention and/or treatment of side effects of ovarectomy or symptoms associated with reproductive senescence in female mammals, in particular urinary incontinence, hot flushes, and skin/hair changes are disclosed.

TECHNICAL FIELD

[0001] The present invention provides pharmaceutical compositions forthe prevention and treatment of side effects of ovarectomy or symptomsassociated with reproductive senescence, especially urinaryincontinence, as well as mood changes, skin changes, hair changes,vasomotor symptoms, especially hot flushes, in mammalian females,particularly in post menopausal women and in spayed bitches. Connectedwith such treatments is the prevention of urinary tract infections.

BACKGROUND OF THE INVENTION

[0002] If the endocrine activity of the gonads decreases or if thegonads are removed, women and dogs show similar changes. With thereproductive senescence in women, as well as after ovarectomy in thebitch, symptoms such as urinary incontinence, vasomotor symptoms, inparticular hot flushes, changes of the mood, skin and hair increasinglyoccur. After ovarectomy, as well as at the beginning of the reproductivesenescence, corresponding hormonal changes occur with a great increasein serum concentrations of FSH (Follicle stimulating hormone) and LH(Luteinising hormone).

[0003] 1. Urinary Incontinence in General

[0004] Urinary incontinence is defined by the International ContinenceSociety [1] as the objective demonstration of involuntary loss of urineconsequent to bladder and/or urethral sphincter dysfunction.

[0005] If the anatomical conditions are normal, two differentpathophysiological mechanisms can lead to urinary incontinence: anincreased tone of the bladder with a normal closure function of theurethra, or an insufficient closure function of the urethra with anormal bladder pressure during the filling phase.

[0006] An insufficient closure function of the urethra plays a crucialrole in both the urinary incontinence in bitches due to spaying and thestress incontinence in women [2] [3] [4].

[0007] 2. Removal of the Ovaries (Spaying) in the Bitch

[0008] Side Effects

[0009] Gonadectomy can lead to side effects. The most common is urinaryincontinence, which occurs in one in five spayed bitches. The continuoushair loss, which is due to the shortened life span of the hairs afterspaying, can be disturbing to the owner. Less common, and mainly inparticular breeds, is the excessive growth of the undercoat which leadsto a “baby-coat”. If food is offered ad libitum the increased appetitecan lead to adipositas and vulvapyodermia. In case of dominant bitchesgonadectomy may increase aggressivity.

[0010] Endocrine Principles

[0011] Twice per year the bitch is on heat for about 3 weeks. Herseasonal mono-oestrous cycle is divided into 4 periods, anestrus,pro-oestrus, oestrus and metoestrus. During anoestrus the plasmaconcentrations of sexual steroids are very low. The level ofprogesterone is below 1 ng/ml, and that of estrogen is below 10 pg/ml.Towards the end of anoestrus, about four weeks before the onset of thenext heat, slight increases in estradiol concentrations can be measured.At the onset of the heat, starting with pro-oestrus, the internalsecretion of estradiol is slightly increased by the growing follicles.At the end of pro-oestrus a sudden increase of the internal estradiolsecretion occurs over two to three days, resulting in a peak serumestradiol of 40 to 90 pg/ml. During the pro-oestrous period thefollicular growth is stimulated by pulsatile FSH and LH release and 24to 72 hours after the last LH-peak ovulation is triggered. The actualoestrus, which is characterized by the bitch's acceptance of the maledog, is dominated by an increasing serum progesterone concentration,whereas the estrogen level returns to basal concentrations of less than10 pg/ml. The corpora lutea produce progesterone for about three months.The progesterone production is independent of whether the bitch ispregnant or not pregnant. The luteal phase is called metoestrus. Afterthe luteolysis, serum progesterone levels are below 1 ng/ml, the bitchis in the period of ovarian quiescence, the anoestrus. During thisperiod the average concentrations of the gonadotropins FSH and LH areabout 114 ng/ml and 1.1 ng/ml respectively [5]

[0012] With gonadectomy the source of the sexual steroids estrogen andprogesterone is removed and afterwards, they are only measurable in verylow serum concentrations that are not different from those measuredduring anoestrus. As there is no longer a feed back mechanism, FSH andLH are secreted unhindered, resulting in average concentrations of 1086ng/ml and 7.4 ng/ml respectively [5]

[0013] Relationship Between Endocrine Changes and Side Effects ofGonadectomy

[0014] Until now, the side effects of spaying have been explained asresulting from the missing estrogen secretion. But various observationsdo not agree with this hypothesis. In sexual intact bitches theendogenous estrogen concentration is elevated only for a short periodonly once or twice per year. In many bitches which are treated withdepot gestagens for suppressing of the estrous cycle for years, theendogenous estrogen concentration is permanently reduced to basallevels. In these bitches with a permanently suppressed ovarian activitymost of the side effects seen after spaying, in particular urinaryincontinence, do not occur. If low estrogen concentrations would beresponsible for the occurrence of urinary incontinence, it could beassumed that the replacement therapy with estrogens would be successful,but in fact, it is effective only in 65% of the cases [6]. Conversely,it would be expected that in sexually intact bitches urinaryincontinence does not occur, especially not during the heat. Apart fromthe many incontinent bitches, due to spaying, seen as patients at theDepartment of Reproduction, University of Zurich, there are severalintact bitches which are incontinent exclusively during estrus.Urodynamic data supports these observations, showing a significantlyreduced urethral closure pressure under the influence of estrogens,during the estrus.

[0015] Urinary Incontinence of the Bitch

[0016] Urinary incontinence is the most common and embarrassing sideeffect of spaying for both the owner and the dog [3]. In all bitchesgonadectomy leads to a significant reduction in the urethral closurepressure within one year. In 20% of the bitches the urethral closurepressure drops below the critical threshold value of 7.5 cm H₂O, leadingto urinary incontinence [3]. Urinary incontinence also has medicalconsequences: Due to the lowered urethral closure function the ascensionof bacteria, leading to an urinary tract infection, is enhanced.Additionally, the continuous contamination of the perineal region withurine can result in skin ulceration.

[0017] Therapy is aimed at improving the urethral closure pressure whichcan be achieved by conservative or surgical methods. First choice arealpha-adrenergic substances such as ephedrinhydrochloride orphenylpropanolamine, at 1.5 mg/kg BW p.o. two to three times per day. Ifthese medications are given every 8 hours, continence was achieved in74%, and at least 24% showed some improvement. But, for the owner it isnot always possible to administer tablets this frequently. Side effectssuch as diarrhea, vomiting, anxiety and nervousness are observed onlyinfrequently. Alpha-adrenergic substances are contraindicated in case ofglaucoma, cardiac arrhythmia and progressive nephropathy. As analternative therapy estrogens can be used, which improve theresponsiveness of catecholamine receptors of the urethra. But givenalone, their effectiveness is inferior to that of the alpha-adrenergicsubstances, for they were found ineffective in 24% of the cases [3]. Thesubstitution with estrogens in dogs can lead to a bone marrowdepression, which can be fatal. Quite a common side effect of theestrogen therapy is recurrence of heat-like symptoms and with it sexualattractiveness to male dogs. These side effects can even be observedafter therapy with phytoestrogens.

[0018] If therapy with medication is unsuccessful, too much trouble tothe owner, accompanied with side effects, or even contraindicated, asurgical or endoscopic procedure can be considered. The injection ofcollagen into the submucosa of the proximal urethra, under endoscopiccontrol, is successful in 75% of the cases and can be repeated ifnecessary. But this therapy requires a full anesthesia, it is expensiveand its success is dependent on the experience of the surgeon. Even moreinvasive, and therefore expensive, is a surgical method, the classicalretropubic urethropexy for incontinent women [7] which has been adaptedfor dogs [8]. This colposuspension, which is performed in fullanesthesia after laparotomy, is only effective in 53% of the dogs withcontinence [9].

[0019] 3. Reproductive Senescence in Women

[0020] Occurrence

[0021] Declining reproductive function is an inevitable part of theaging process [10]. The dramatic endocrine changes brought about byreproductive senescence have biological, social and culturalimplications that profoundly influence the latter half of a woman'slife.

[0022] Symptoms

[0023] Women may experience a number of symptoms such as hot flushes,mood changes and altered sleep pattern during the transition from thereproductive to the non-reproductive stage of life. Menopause isassociated with an accelerated bone loss which may lead to thedevelopment of osteoporosis in women. Vaginal dryness with its sequelae,such as urogenital infections and impaired sex life, are well knownproblems of menopause. The incidence of urinary tract infectionsincreases in women with increasing age.

[0024] Correlation Between Endocrine Changes and Symptoms of theReproductive Senescence

[0025] As one of the first signs of the impending transition tomenopause, in middle aged regularly menstruating women, the frequency ofLH pulses decreases and the width of the peak increases before anychange in the amount of plasma estradiol [11]. These changes areaccompanied by elevated FSH concentrations during the early follicularphase [12] [13] [14].

[0026] Following, on the one hand there is a continuous increase ofserum PSH and LH, while on the other hand a concomitant decrease inestradiol and estrone can be observed, as yearly examinations of womenhave shown during the transition from the reproductive to thenon-reproductive stage of life [15]. Initial symptoms of thereproductive senescence, such as hot flushes and sweating, already occurin normocycling women and were significantly associated with high levelsof FSH and LH and with low levels of estradiol [16]. Exacerbation of thesymptoms was consistent with changes in gonadotropin levels [17] [18].

[0027] Urinary Incontinence in Women

[0028] Urinary incontinence also affects many women of all age groups.The prevalence of incontinence has been estimated to be between 9 and74% [19] [20] [21] [22] [23] [≧] [25].

[0029] Until now, the etiology of urinary incontinence is notelucidated, but most likely is caused by several factors. Differentstudies have shown a correlation between the risk of urinaryincontinence and age [26], number of births [20], age of giving birth[25], body mass index [23] [25], race [23] level of education [25],frequency of bed-wetting during childhood [25], physical exercise ormenopausal estrogen deficiency [12]. With the development of menopausethe frequency of lower urinary tract symptoms, such as urgency,hesitancy and frequency, seem to increase. [27]

[0030] The difference of the mean maximum urethral closure pressure is20 cm H₂O between continent and incontinent women of corresponding age.The closure function of the urethra deteriorates in an age dependentrelationship in a similar way in continent as well as incontinent women,but is based on different initial values [28] [29] [2] [30].

[0031] Urinary incontinence predisposes to urinary tract infections,pressure ulcers, perineal rashes, and urosepsis.

[0032] 4. Comparison of the Reproductive Senescence in Women and theSide Effects of Spaying in the Bitch

[0033] The symptoms associated with reproductive senescence in womenhave amazing similarities with the side effects of spaying in the bitch.In both species there is an increased incidence of vaginal dryness, moodand behavioral changes, and urinary incontinence. A characteristicfeature of urinary incontinence in women, as well as in dogs, is areduced urethral closure function. In the bitch, spaying is proven to bethe trigger for urinary incontinence.

[0034] Until now, neither the pathophysiological correlation betweenspaying and urinary incontinence in the bitch nor the cause of urinaryincontinence in women is elucidated. But it can be assumed that similarmechanisms are involved, because for conservative treatment the samesubstances are recommended in both species.

[0035] In reproductive senescence in women as well as after spaying ofbitches the levels of FSH and LH increase many times. Because LHreceptors are not limited to the genital tract [31] [32] but are alsofound, among others, in the urinary bladder [33] and the skin [34], acorrelation between the increased FSH- and LH levels and the clinicalchanges after menopause or spaying is most likely. In post menopausalwomen the number of LH receptors in the bladder decreases, most likelybecause of a down-regulation of the LH receptors by increasedgonadotropin levels [33]. A down-regulation of receptors is also knownto occur on a higher level, for example the pituitary gland. Prolongedexposure of GnRH receptors to GnRH results in loss of responsiveness tothe hormone, through receptor alteration [35]. The outcome of such adown-regulation of sensitivity to GnRH results in a suppression ofcirculating levels of gonadotropins [36] [37] [38] [39] [40] [41].

[0036] Despite recent progress in understanding the pathophysiology ofurinary incontinence, successful management continues to be a challenge.Medical treatment for urinary incontinence in women, or urinaryincontinence in the bitch, include estrogen and/or progesteronereplacement, supplementation with alpha-adrenergic agonists,beta-adrenergic receptor blocking agents, cholinergic receptor blockingcompounds, cholinergic receptor stimulating drugs, nitric oxide synthasesubstrates, nitric oxide donors or both. Other treatment proceduresinclude behavioral therapy, nerve stimulation, injection therapy,mechanical devices [42] [43] and surgery.

[0037] The hitherto existing medical treatments for incontinence haveeither unsatisfactory success or show severe side effects and cantherefore not be administered to patients with e.g. glaucoma, hypertoniaand cardiac arrhythmias. Therefore there exists a great need ineffective pharmaceutical compositions and medicaments for the successfultreatment or prevention of incontinence in female mammals with minimaladverse effects on the treated individual.

[0038] It has now surprisingly been found that a compound, or apharmaceutical composition comprising a compound that modulates thelevel of biologically active gonadotropins is an effective medicamentfor the treatment or prevention of urinary incontinence in femalemammals.

DISCLOSURE OF THE INVENTION

[0039] Hence it is an object of the present invention to use at leastone GnRH analogue for the preparation of a medicament for the treatmentand/or prevention of side effects of ovarectomy or symptoms associatedwith reproductive senescence in female mammals.

[0040] The term GnRH analogue as used herein encompasses GnRH agonistsand GnRH antagonists. A GnRH antagonist is a compound which suppressesthe activity of GnRH by e.g. binding the GnRH receptors on target cellsand thereby blocking its biological activity or which decreases theproduction/release of endogenous GnRH. A GnRH agonist is a compoundleading to a temporary overproduction of gonadotropins which leads to adownregulation of at least one gondadotropin i.e. FSH and/or LH.

[0041] The term GnRH analogue comprises compounds such as e.g.antibodies against GnRH and compounds leading to a cessation of GnRHproduction due to the use of a specific antisense gene construct.

[0042] Said GnRH analogue is preferably selected from the groupconsisting of peptides, polypeptides and proteins.

[0043] Side effects and symptoms in the scope of the present inventioncomprise vasomotor symptoms, especially hot flushes, mood changes, suchas e.g. depression and aggressivity, skin changes, hair changes, and inparticular urinary incontinence.

[0044] For specific treatments, a medicament of the present inventionmay comprise at least one further active compound selected from thegroup consisting of: an estrogenic agent, a partial estrogenic agent, aprogestational agent, alpha adrenergic agonist, beta-adrenergic receptorblocking agent, cholinergic-receptor blocking compound,cholinergic-receptor-stimulating drug, smooth muscle relaxant, nitricoxide substrate, nitric oxide donor, and mixtures thereof.

[0045] A medicament comprising a second and/or further active compoundmay be, and preferably is, a combination of specific dosage units,comprising a first dosage form for the GnRH analogue, e.g. a slowrelease dosage form, and at least one further dosage form comprising oneor more further active compounds, whereby said first and said seconddosage form may be administered at the same, or at different times, andwith the same or different frequencies.

[0046] In another aspect, the present invention relates to a method forthe treatment and/or prevention of side effects of ovarectomy orsymptoms associated with reproductive senescence in female mammals, inparticular incontinence, said method comprising the administration of acomposition or a medicament of the present invention to an individual inneed thereof.

[0047] Upon further studies of the specification and appended claims,further aspects, objects and advantages of this invention will becomeapparent to those skilled in the art.

MODES FOR CARRYING OUT THE INVENTION

[0048] Thus, this invention relates to the use of a GnRH analogue forthe preparation of a medicament for treating and/or preventing sideeffects of ovarectomy or symptoms associated with reproductivesenescence, in particular urinary incontinence and vasomotor symptoms,in female mammals, in particular women and bitches.

[0049] Preferably, the amount of said at least one GnRH analogue iseffective to improve the side effects of ovarectomy or symptomsassociated with reproductive senescence, in particular urinaryincontinence or vasomotor symptoms, by changing the pulsatile and tonicpattern of FSH and/or LH release and/or lowering the blood-level ofcirculating FSH and/or LH in a female mammal to whom the composition isadministered.

[0050] By the methods of the present invention side effects ofovarectomy or symptoms associated with reproductive senescence, inparticular urinary incontinence and vasomotor symptoms, in femalemammals, in particular women and bitches, which are manifesting thesymptoms thereof, can be treated and prevented.

[0051] Because the conditions of reproductive senescence and the sideeffects of ovarectomy are produced or aggravated by changes in thepulsatile patterns of FSH and LH and/or elevated FSH and/or LH-levels,one or more compounds leading to a decreased synthesis or a decreasedrelease of said hormones such as e.g. deslorelin, goserelin, buserelin,triptorelin, leuprolid or their acetates or a combination of them areuseful for ameliorating the side effects of ovarectomy or symptomsassociated with reproductive senescence.

[0052] In certain cases an additive effect can be achieved and theseverity of the symptoms can be decreased when a estrogenic agent isadministered concurrently with said GnRH analogue. In the case of afemale mammal, an estrogen or a progestin can be administered, or anestrogen can be administered concurrently with a progestin.

[0053] In other cases an additional effect can be achieved and theseverity of the symptoms can be decreased when said at least one GnRHanalogue is administered either with estrogen or progestin andsupplemented with at least one compound selected from the groupconsisting of: alpha-adrenergic agonists, beta-adrenergic receptorblocking agents, cholinergic receptor blocking compounds, cholinergicreceptor stimulating drugs, smooth muscle relaxants, nitric oxidesubstrates and/or nitric oxide donor receptors.

[0054] Thus, the method aspects of this invention and the medicamentaspects of this invention employ one or more GnRH analogue andoptionally one or more of, e.g. an estrogen (e.g. Progynova, Schering)or a progestin (e.g. progesterone, norgestrel, proligeston,medroxypro-gesteronacetate, chlormadinaonacetate), with or without atleast one compound selected from the group consistingof:alpha-adrenergic agonists, beta-adrenergic receptor blocking agents,cholinergic receptor blocking compounds, cholinergic receptorstimulating drugs, smooth muscle relaxants, nitric oxide substratesand/or nitric oxide donor receptors.

[0055] Examples of typical substances leading to a decreased bloodconcentration of FSH and LH are:

[0056] Deslorelin acetate, Goserelin acetate, Nafarelin acetate,Buserelin acetate, Triptorelin acetate, Gonadorelin acetate, Leuprolidacetate, Danazolum, and Cetrorelix.

[0057] The amounts may be in the range known for down-regulation ofLH/FSH, whereby the amount depends e.g on the formula, the intervalls,the root of administration and the responsiveness of the individual. Forexample Deslorelin acetate usually is administered to bitches in amountsof 1 to 100 mg, preferably 3 to 20 mg at intervalls from 1 month to 2years. The amount depends on the dog's size, whereby the amount usuallyis at least about 0.1 mg/kg, preferably at least 5 mg/kg.

[0058] Substances leading to a decreased concentration of Folliclestimulating hormone (FSH) and/or Luteinizing hormone (LH) and/or to adecreased or increased concentration or activity of Gonadotropinreleasing hormone (GnRH) can be administered preferentially by asubcutaneous or intramuscular implant.

[0059] Examples of second or further active agents, or combinationsthereof which can be administered concurrently with a GnRH analogue areestrogens, partial estrogen agonists (partial estrogens), andprogestins.

[0060] Estrogens and/or partial estrogens and/or progestins—if any—areusually administered to supplement endogenous production, the amount ofestrogen being bioequivalent to approximately 0.005 mg-2 mg per day ofestradiol (e.g. Progynova, Schering), the amount of a partial estrogenbeing bioequivalent to approximately 0.002 mg-200 mg per day of e.g.raloxifene, and the amount of the progestational agent administeredbeing bioequivalent to 50-300 mg of injected progesterone.

[0061] Estrogens may e.g. be administered as estradiol, estradiolvalerate, estradiol hemihydrate, vaginal estradiol tablets, vaginalestradiol creams and/or vaginal estradiol rings.

[0062] Partial Estrogen Agonists (partial estrogens) are e.g.raloxifene, tamoxifen, nafoxidin, centchroman, and toremifen.

[0063] Further optionally present agents include:

[0064] Alpha-adrenergic-receptor-agonists, e.g. Phenylpropanolamine andPhenylephrine;

[0065] Beta-receptor-blocking agents, e.g. Propranolol, Befaxolol,Acebutolol, Atenolol, and Bisoprolol;

[0066] Cholinergic-receptor blocking compounds, e.g. Benztropine,Biperiden, and Propantheline;

[0067] Cholinergic-stimulating drugs, e.g. Bethanecol andNitroglycerine.

[0068] Combinations of smooth muscle relaxants and anticholinergics mayalso be present and comprise e.g. oxybutynin, dicyclomine, andflavoxate. Such smooth muscle relaxants, may be combined with e.g.anticholinergics and α-adrenergics such as imipramine and/ordesipramine.

[0069] Many other examples of compounds in each of the foregoingcategories are well known and can be employed in this invention in theabove described combination.

[0070] A GnRH analogue can be administered either alone, or incombination with other active substances, in admixture with conventionalexcipients, i.e., pharmaceutically acceptable liquid, semi-liquid orsolid organic or inorganic carriers, in particular carriers suitable,e.g., for parenteral or enteral application. It goes without saying thatsuch carriers are much preferred that do not deleteriously react withthe active compound in admixture therewith. Suitable pharmaceuticallyacceptable carriers include but are not limited to water, saltsolutions, alcohols, vegetable oils, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinylpyrrolidone, etc.

[0071] The pharmaceutical preparations can be and preferably aresterilized. The pharmaceutical preparations can—if desired—be mixed withauxiliary agents, e.g., lubricants, preservatives, stabilizers, wettingagents, emulsifiers, salts for influencing osmotic pressure, buffers,coloring, flavoring and/or aromatic substances and the like which do notdeleteriously react with the active compounds.

[0072] For parenteral application particularly suitable are solutions,preferably oily or aqueous solutions, as well as suspensions, emulsions,or implants, including transdermal patches, and vaginal gels, creams andfoams. Ampoules are convenient unit dosages. Another suitable dosageform, especially for long lasting effects, are microencapsulated drugs.

[0073] For enteral application, particularly suitable are unit dosageforms, e.g. for rectal application suppositories, for oral applicationtablets, dragees, capsules or, having talc and/or carbohydrate carrieror binder or the like, the carrier preferably being lactose and/or cornstarch and/or potato starch; particulate solids, e.g., granules; andliquids and semi-liquids, e.g., syrups and elixirs or the like, whereinpreferably a sweetened vehicle is employed. Sustained releasecompositions can be formulated including those wherein the activecompound is protected with differentially degradable coatings, e.g., bymicroencapsulation, multiple coatings, etc.

[0074] Suitable for oral administration are, inter alia, tablets,dragees, capsules, pills, granules, suspensions and solutions.

[0075] As already mentioned above, a GnRH analogue can be administeredas an admixture with an estrogen and/or partial estrogen and/orprogestational agent and/or any other optional active agent, or it canbe administered as a separate unit dosage form, either simultaneouslywith a unit form of a second and/or further active compound at the sametime or at different times during a day, or at different days, and withthe same or different intervals.

[0076] For administration by injection or implant the active agents arepreferably formulated as slow release formulations which deliver theactive agents continuously. Such formulations may be designed fordifferent frequencies of administration such as once a day, once a week,once a month, once all six months, once a year, or even foradministration at larger intervals, whereby administration once all sixmonths to once a year is presently preferred.

[0077] If administration by injection or implant at intervalls of e.g.six months to one year is chosen for the GnRH analogue, a second orfurther active substance may be administered at shorter intervalls, e.g.in the form of tablets thereby allowing easy adaptation of the dosage ofone such substance or the sequential administration of differentsubstances in the same or different dosages, e.g. to better react onnaturally occurring hormonal changes. The frequency of suchadministration of a second and/or further active substance may e.g. beonce a day, once a week, once a month etc.

[0078] In mammals, suitable ratios at which an at least one GnRHanalogue should preferably produce in humans FSH and LH blood plasmalevels <3 IU/l or <6 IU/l respectively.

BRIEF DESCRIPTION OF THE EXPERIMENTS

[0079] Fifteen bitches suffering from urinary incontinence afterspaying, which did not respond to or tolerate an other incontinencetreatment before, such as a treatment with ephedrine, estrogen,flavoxate, phenylpropanolamine or collagen deposits, were firstclinically examined and thereafter a GnRH analogue in a dosage of3.75-12 mg, in slow release form, was subcutaneously implanted betweenthe shoulder blades. Additionally, for a limited period the dogs weretreated with phenylpropanolamine in a dosage of 1.5 mg/kg BW tid orally.Combined treatment completely resolved the incontinence in 12 bitchesand in one bitch the incontinence was significantly less severe. Onlytwo dogs out of fifteen did not respond with an improvement incontinence, whereby one of said dogs was treated with an amount belowthe proposed minimal dosage.

[0080] After discontinuation of the shortacting phenylpropanolamine 8bitches remained continent. Their continence was therefore achievedsolely by the treatment with the composition as described in the presentinvention. Seven out of fifteen dogs seemed to be much happier and innone of the dogs did the general condition deteriorate. Three dogs,which were aggressive against other dogs before the treatment, were lessaggressive against other dogs after the treatment. The respectiveresults are shown in more detail in table 1.

[0081] In a second ongoing study, 16 client owned dogs suffering fromurinary incontinence were enrolled in a double-blind, placebo-controlstudy. In the initial phase of the study, dogs were randomly assigned totreatment with a long-acting GnRH analogue (leuprolide acetate) orplacebo (dog owners and the investigators were blinded to treatment)along with a short course of therapy with phenylpropanolamine. 5 weeksafter treatment with drug or placebo, dogs were evaluated and, if notfully continent, treated with a long-acting GnRH analogue (leuprolideacetate) in an open label phase of the study. To date only 1 of 10 dogstreated with placebo became continent vs. 3 to 8 dogs treated with drugduring the blinded portion of the study. Overall, the results generatedthus far indicate 6 of 15 dogs treated with the long-acting GnRHanalogue became continent and 9 of the remaining dogs improved afterdiscontinuation of the short acting phenylpropanolamine. Only 1 dog of15 treated with the GnRH analogue was considered not to have improvedfollowing treatment with the drug.

[0082] Two cocker spaniel bitches belonging to the same owner wereshowing excessive growth of the undercoat due to spaying. One of thesesdogs did not tolerate estrogen treatment before. Both dogs were firstclinically examined and thereafter a GnRH analogue (Deslorelin) in adosage of 5 mg, in slow release form, was subcutaneously implantedbetween the shoulder blades. 5 weeks after the injection an obviousamelioration of the coat quality was seen in both dogs, 21 weeks afterinjection no signes of “baby coat” were apparent anymore.

[0083] As use in humans is concerned, a perimeno-pausal woman with urgeincontinence and hotflushes reported both symptoms improved considerablyfor a period of about 4 weeks after treatment with 3.75 mgtriptorelinacetate. A second menopausal woman, suffering from stressincontinence for at least 6 years, was treated with a single dose of3.75 mg of leuprolide acetate. 24 hour pad tests conducted prior totreatment with the drug indicated she lost between 10 and 130 ml ofurine on a daily basis due to her incontinence. A pad test conducted 2weeks after treatment with leuprolide acetate indicated daily urine losshad decreased to only 1 ml of urine and the patient claimed to be verysatisfied with the effects of the therapy.

[0084] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0085] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. TABLE 1 Duration of Duration dog incontinence Effect on ofeffect weight prior to inconti- after (kg) treatment Other problemsTreatment Side effects nence treatment Comments 44 2 years No 6 mgDesloreli- — 100% >344 d nacetate 28 10 months Atopy 6 mg Desloreli-More playfull 100% >340 d nacetate 6 2 years Too short ure- 6 mgDesloreli- with PPA >336 d thra nacetate 100% 28 4 years Timid 12 mgDeslore- More self- with PPA 135 d Collagen linacetate assured 80% 60 2,3 years Cardiomyopathy, 12 mg Deslore- — 100% 64 d Euthana- Vaginitislinacetate tized osteo- sarcoma 28 2 years proteinuria 12 mg Deslore- —100% >64 d linacetate 32 5 years — 12 mg Deslore- with PPA >318 dlinacetate 100% 20 2 years Isosthenuria, 12 mg Deslore- More tolerantwith PPA >225 d polydipsia linacetate against males 100% 40 1 monthsAggressive 12 mg Deslore- less aggressive 100% >209 d linacetate moreactiv 36 4 months polydipsia, 3,75 mg — Not effec- 0 * dose timidTripto- tive too low relinacetate * 60 2 years 6,3 mg Busere- — 100% 44d linacetate 28 2 years sebaceous ade- 6,3 mg Busere- agile, more 100%83 d nitis epilepsia linacetate playfull 6 mg Desloreli- agile, more100% >47 d nacetate playfull 30 1, 5 years 11,25 mg Leu- Better mood Noteffec- 0 prorelinace- tive tate 25? 4 months proteinuria 11,25 mg Leu-Less aggressiv with PPA >64 d prorelinace- 100% tate 18? 21 months 11,25mg Leu- — 100% >14 d prorelin ace- tate

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1. Use of at least one GnRH analogue for the preparation of a medicamentfor the treatment and/or prevention of side effects of ovarectomy orsymptoms associated with reproductive senescence in female mammals. 2.Use according to claim 1 wherein said GnRH analogue is selected from thegroup consisting of peptides, polypeptides or proteins.
 3. Use accordingto claim 1 or 2 wherein the side effects or associated symptoms to beprevented or treated are clinical signs such as vasomotor symptoms,especially hot flushes, mood changes, such as e.g. depression andaggressivity, skin changes, hair changes, urinary incontinence orcombinations thereof.
 4. Use according to claim 3 wherein the sideeffects or associated symptoms to be prevented or treated is urinaryincontinence.
 5. Use according to claim 3 wherein the side effects orassociated symptoms to be prevented or treated are vasomotor symptomssuch as hot flushes.
 6. Use according to anyone of the preceding claimscharacterized in that said GnRH analogue is selected from the groupconsisting of deslorelin acetate, goserelin acetate, nafarelin acetate,buserelin acetate, triptorelin acetate, gonadorelin acetate, leuprolidacetate, danazolum, Cetrorelix or mixtures thereof.
 7. Use according toanyone of the preceding claims wherein said medicament comprises afurther active substance selected from the group consisting of anestrogenic agent, a partial estrogenic agent, a progestational agent andmixtures thereof.
 8. Use according to claim 7, characterized in that theestrogenic agent is selected from estradiol valerate, a conjugatedequine estrogen, 17β-estradiol, estrone and estriol; the partialestrogenic agent is selceted from raloxifene, centchroman, toremifen andtamoxifen; and the progestational agent is selected from progesterone,hydroxygesterone, medroxyprogesterone, norethisterone, levonogestrel,norgestrel, gestodene and drospirenone.
 9. Use according to anyone ofthe preceding claims, characterized in that said medicament comprises afurther active substance selected from the group consisting ofalpha-adrenergic agonist, beta adrenergic receptor blocking agent,cholinergic receptor blocking compound, cholinergic receptor stimulatingdrug, smooth muscle relaxant, nitric oxide synthase substrate and anitric oxide donor, and mixtures thereof.
 10. Use according to anyone ofthe preceding claims wherein said medicament comprises different unitforms, at least one for the at least one GnRH analogue and at least onefor an at least one further active substance.
 11. Use according toanyone of the preceding claims wherein said medicament is a slow releaseformulation for at least the GnRH analogue.
 12. Use according to anyoneof claims 1 to 6 wherein said medicament comprises as active compoundsonly at least one GnRH analogue.
 13. Use according to anyone of thepreceding claims, characterized in that the female mammal is a humanfemale pre-or postmenopausal, or a female dog.
 14. Use according toanyone of the preceding claims, characterized in that the medicament isa formulation for subcutaneous administration.
 15. Use according toanyone of claims 1 to 13, characterized in that the medicament is aformulation for parenteral, oral or rectal administration.
 16. Useaccording to anyone of claims 1 to 13, characterized in that themedicament is a formulation for intranasal, transdermal or intravaginaladministration.
 17. A method for the treatment and/or prevention of sideeffects of ovarectomy or symptoms associated with reproductivesenescence in female mammals, said method comprising the administrationof a medicament of anyone of claims 1 to 16 to an individual in needthereof.
 18. The method according to claim 17, characterized in that themedicament is administerd subcutaneously.
 19. The method according toclaim 17, characterized in that the medicament is administeredparenterally, orally or rectally.
 20. The method according to claim 17,characterized in that the medicament is administered transdermally,intravaginally or intranasally.